Basic amides of 1-aryl-cycloalkyl-1-carboxylic acids



Patented Mar, 9, 1948 BASIC AMIDES OF l-ARYL-CYCLOALKYL-l- CARBOXYLICACIDS Henry Martin and Franz Hafliger, Basel, Switzerland, assignors toJ. R. Geigy A.-G., Basel,

Switzerland, a firm No Drawing. Original application June 2, 1944,

Serial No. 538,542. Divided and this application July 26, 1945, SerialNo. 607,274

6 Claims. (01.260-558) The present application is a divisional patentapplication of our copending application Ser. No. 538,542, filed on June2, 1944, now U. S. Patent 2,404,588, as a continuation-in-partapplication of our application Ser. No. 506,760jfiled on October 18,1943, which is abandoned.

Therapeutlcally valuable compounds selected from the series of thecycloalkyl-monocarboxylic acids or of their homologues and substitutionproducts respectively have not become known hitherto. It has now beenfound that the basic amides of cycloalkyl-l-carboxylic acids arylated inl-position possess very valuable therapeutical properties. Thesecompounds are produced by aminating the carboxylic acids with suitablediamines.

For the preparation of the amides either 1- aryl-cycloalkyl-l-carboxylicacids are interacted with alkylene diamines containing a primary orsecondary and at least one tertiary amino group, or reactive esters ofcorresponding amino alcohols are caused to react with metal salts,especially with alkali salts of l-arylated cycloalkyl-lcarboxylic acidamides. The amides are also obtained in an indirect manner byinteraction of the cycloalkyl carboxylic acids or derivatives orsubstitution products thereof with amino alcohols having a primary orsecondary amino group or by causing alkylene halogen hydrines oralkylene dihalides to react with amides of cycloalkyl-l-carboxylic acidsarylated in l-position and containing 1 to 2 hydrogen atoms in the amidegroup, or in some cases also with metal compounds of the said amides,and replacing the external substitutent in the so-obtained hydroXy alkylor esterified hydroxy-alkyl amides by a disubstituted amino groups.

By addition of alkyl halides, alkylene halides, aryl sulphonic acidesters, dialkyl sulfates, aralkyl halides and so on the quaternarycompounds of the above amides are obtained in the usual manner. If, forthe conversion of the cycloalkyl-carboxylic acid, halogen alkyl amides,tertiary amines, like trimethyl amine or triethylamine, are used, thequaternary ammonium compounds are directly obtained.

The l-aryl-cycloalkyl-l-carboxylic acids are mostly known; the compoundsnot known hitherto can be produced in the same manner like thecorresponding products described in the literature.

The present invention may be illustrated, but not limited, by thefollowing examples, the parts being by weight, unless otherwise stated.

Example 1 20.8 parts of l-phenyl-l-cyclopentyl-1-carboxylic acidchloride. obtained from the acid (cf. Am. Soc., 1934, 56, 715) by meansof thionylchloride, are dissolved in 200 parts by volume of absolutebenzene; then, a solution of 12 parts of N,N-diethyl ethylene diamine inparts by volume of absolute benzene is allowed to drop thereinto,whereupon the whole mixture is heated for 10 minutes under reflux. Thehydrochloride of the new base which is formed is filtered on anddissolved in water. The aqueous solution is made alkaline with potassiumcarbonate solution and shaken out with ether; the etheral solution iswashed with water, dried over potassium carbonate andthe solvent isdistilled 011. The base boils at 0.03 mm. pressure at -l42 C.

20.8 parts of 1-phenyl-cyclopentyl-l-carboxylic acid chloride and 13parts of N:N-diethyl-N- methyl ethylene diamine lead to a base of theboiling point of 138-140 C. at 0.05 mm. pressure.

When using 25 parts of 1-(3:4-dimethylphenyl)-cyclohexyl-1-carboxylic'acid chloride and 15 parts of N:N-diethyl-N'-ethyl ethylene diamine,there results a base of the boiling point of 159-- 161 C. at 0.04 mm.pressure.

Example 2 40 parts of l-phenyl-cyclohexyl-l-carboxylic acid amide and 8parts of sodium amide are heated for 6 hours to boiling under reflux in400 parts of toluene, whereupon the calculated quantity of,B-chloroethyl diethyl amine is slowly added thereto and the whole isfurther heated, until the reaction is completed. After cooling, thetoluene solution is shaken with diluted hydrochloric acid and the newbase separated in the usual manner from the filtered, aqueous solution.The 1- phenyl-cyclohexyl 1 carboxylic acid diethyl amino ethyl amideboils at'0.03 mm. pressure at 148150 C.

The same base can also be produced by heatingl-phenyl-cyclohexyl-l-carboxylic acid with 2-diethylamino ethyl amine to200 C. or by boiling for several hours the methyl or ethyl ester of thecorresponding acid with the amine.

By the analogous condensation of l-phenylcyclopentyl-l-carboxylic acidamide, l-phenylcyclopentyl-l-carboxylic acid methyl or ethyl amide aswell as of 1-phenyl-cyclohexyl-1-carboxylic acid methyl or ethyl amidewith diethyl amino ethyl chloride the corresponding amides are obtained.

Example 3 41 parts of l-phenyl-cyclopentyl-l-carboxylic acid and 12parts of amino ethanol are heated for 2 hours at 200 C., the water beingformed during the condensation being allowed to distil off. Aftercompletion of the interaction the resuitingl-phenyl-cyclopentyl-l-carboxylic acide-hydroxy ethyl amide is dissolvedin chloroform and heated tor 2 hours at 60 G. with the calculatedquantity of phosphorus pentachloride, The reaction mass is extractedwith ether, the ethereal solution washed with sodium carbonate and waterand then dried over potassium carbonate. After evaporation of thesolvent, the l-phenylcyclopentyl 1 carboxylic acid p chloroethyl amideis obtained as a bright oil. r

27.5 parts of this compound are heated for 10 hours to 130 C. with 18parts of diethyl amine. Then it is dissolved in diluted hydrochloricacid, filtered and the 1-phenyl-cyclopentyl-l-carboxylic acid diethylamino ethyl amide is precipitated from the aqueous solution by means ofsodium carbonate. The base possesses the boiling point of 140-142 C. at0.03 mm. pressure.

Instead of phenylecycloalkyl carboxylic acids the analogous compounds ofthe naphthalene series, such as for instance l-rxorl-p-naphthylcyclohexyl-lecarboxylic aoid,pcan be used likewise.

What we claim is:

1. The basic amides of learylecycloalkyl-lcarboxylic acids of thegeneral formula wherein aryl means a member selected from the groupconsisting of the unsubstituted phenyl radicals and the phenyl radicalssubstituted by methyl groups, R means a member of the group C 3 CH3 Ha-Ha being a colorless liquid boiling at -142 C. at 0.03 pressure.

5. The 1- (3' :4'-dimethylphenyl) -cyclohexyll-carboxylic acidN':N-diethylamino ethyl-(N- ethyl) -amide of the formula CzHs being acolorless liquid boiling at l59-161 C. at

0.04 mm. pressure.

6. The 1-pheny1-cyclopentyl-1-carboxy1ic acid N :N'-diethylamino ethyl-(N-methyl) -amide of the formula being a liquid boiling at 138-140 C. at0.05 mm.

pressure.

HENRY MAR'I'JN. FRANZ HAFLIGER.

REFERENCES CITED The following references are of record in the file ofthis patent:

Switzerland Oct. 16, 1941

